Current influenza vaccination using needle injections requires annual updates of vaccine strains and imposes a tremendous burden on healthcare workers worldwide. Oral vaccination, which is a very convenient and safe route for vaccination, could improve the prevention of mucosal infection by influenza viruses. However, it is a challenging problem to stabilize the vaccine antigens in the harsh environment of stomach and to target them to the immune system of intestines. Our preliminary studies provide evidence that inactivated influenza vaccines can provide heterosubtypic cross protection if their immunogenicity is enhanced, and that oral vaccination can confer protective immunity. In our quest to advance to the next generation of vaccines using novel nanotechnology formulation, we propose to encapsulate influenza vaccines into stabilized small beadlike particles containing microspheres and nanospheres for oral vaccine delivery. Oral vaccines to be tested include the currently licensed forms of inactivated and live vaccines against the 2009 pandemic influenza virus. The main focus in aim 1 will be to encapsulate the influenza vaccines with an acid resistant material to stabilize vaccine antigens in the gastric environment, and the ligands, strategically targeting them to the intestinal immune system of Peyer[unreadable]s patches and M cells. In Aim 2, we will determine the breadth of cross protective efficacy with promising influenza oral vaccine candidates using the human H1N1 isolate of the 2009 pandemic influenza virus, and heterologous and heterosubtypic influenza strains in a mouse model. In addition, we will evaluate the efficacy of oral vaccination in ferrets, which is a more relevant animal model for testing pre-clinical influenza vaccines for humans. It is expected that improved oral vaccination will provide protection against the strains including the 2009 H1N1 influenza virus, which would have significant implications for clinical applications and for improving the public health.